Radiation therapy acts not only on tumor cells but also on the tumor vasculature. Thus, to optimize tumor treatment it is important that this multi-targetability be considered and exploited. Both experimental and theoretical methods are needed to sort out the dynamic interactions between the endothelial and tumor cells under treatment. Radiation is known to induce pro-angiogenic growth factors (e.g. VEGF) that both protect tumor endothelial cells from radiation killing and promote neovascularization. We hypothesize that following irradiation these same factors can lead to increased production of circulating endothelial cells (CECs) to fuel tumor growth. Thus, the use of exogenous blockers of these factors during or after radiation treatment may enhance the efficacy of radiation by blocking both survival of endothelial cells local to the tumor and the production of CECs. Using lung cancer models, we examine the use of novel antiangiogenic agents in combination with radiation to study the modulation of radiation killing of endothelial cells. We propose to exploit and increase endothelial killing and CEC repression and thereby enhance radiation efficacy by treatment with small-molecule VEGF receptor tyrosine kinase blockers currently under clinical study. The VEGFR inhibitors will be tested concurrently with and subsequent to radiation. To this end, we will investigate, in vivo and in vitro, the time-dependent expression of the pro-angiogenic factors following irradiation. We will also examine genome-wide array response of: 1) different tumor cell compartments (e.g. the endothelial-cell and tumor-cell compartments) following irradiation w/o the antiangiogenics under study, and additionally, 2) the endothelial-cell compartment following each VEGF and VEGFR-tyrosine kinase inhibitor perturbation. The restructuring and regression of tumor vascular in response to treatment will be tracked by imaging. Since it is now recognized mat endothelial cells arising in the bone marrow circulate and are recruited to sites of injury, levels of CECs will be studied to determine the relative roles of on-site vs. circulating endothelial cells in tumor response following these treatments. To determine the reciprocal influence of the different tumor compartments to therapeutic response, 'the Pi's theoretical model of tumor/vascular growth that takes into account cross-talk between tumor-cells and endothelial cells will be extended and our empirical data will be incorporated. This mathematical model is instrumental for associating mechanistics (e.g. ratios of tumor to endothelial cell killing) with therapeutic response. Lung cancer models are used in this investigation because effective adjuvant treatments for chemoradiotherapy in lung cancer are badly needed. These studies will therefore have significant translational as well as scientific relevance.